MicroRNAs (miRNAs) have recently emerged as a major class of trans-factors that regulate expression of protein coding genes at the mRNA level, thereby controlling a diverse range of biological processes including cell differentiation, proliferation, and apoptosis. Genetic studies from us and other groups have demonstrated that miRNAs are involved in the control of lymphocyte development and function, as well as in autoimmune diseases. However, the specific functions of individual miRNAs in the immune system remain largely unknown. We propose to use a newly developed lentiviral miRNA expression library, the recently published miRNA sponge technology, and a unique mouse model of B cell tolerance to systematically assess the functions of miRNAs in B cell development and tolerance. The primary goal of this proposal is to identify miRNAs that play important roles in B cell development and tolerance and, by doing so, to open up new avenues for in-depth studies of specific functions and molecular mechanisms of individual miRNAs in the future. PUBLIC HEALTH RELEVANCE: The initial impact of the proposed research will be on advancing our understanding of the relationships between particular miRNAs and lymphocyte development and immune tolerance. In the long run, the miRNAs that we uncover during these experiments may themselves be valuable diagnostic markers and possible targets of therapeutics for autoimmune diseases, organ transplantation, and cancer immune therapy. Furthermore, target identification for these miRNAs will lead to the discovery of protein coding genes that make ideal targets for therapeutic interventions.